NEW ZEALAND DATA SHEET 1. PRODUCT NAME COMBIGAN® brimonidine tartrate 0.2% and timolol (as maleate) 0.5% eye drops 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of COMBIGAN® eye drops contains brimonidine tartrate 2.0 mg/mL and timolol (as maleate) 5.0 mg/mL For the full list of excipients, see section 6.1 3. PHARMACEUTICAL FORM Sterile ophthalmic solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications COMBIGAN® eye drops are indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension not adequately responding to monotherapy. 4.2 Dosage and method of administration The recommended dose is one drop of COMBIGAN® in the affected eye(s) twice daily, approximately 12 hours apart. In order to minimise systemic absorption of COMBIGAN® eye drops, apply pressure to the tear duct immediately following administration of the drug. As with all eye drops containing benzalkonium chloride as a preservative, there is potential for incompatibility with other topical ophthalmic medications. If more than one topical ophthalmic drug is to be used, other eye drops should not be used within five to ten minutes of using COMBIGAN® eye drops. To avoid contamination of the solution, keep container tightly closed. Do not touch dropper tip to any surface. Discard contents 4 weeks after opening the bottle. Contents are sterile if seal is intact. Paediatric Use Safety and effectiveness in paediatric patients have not been established. During post- marketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression and somnolence have been reported in neonates, infants and children receiving brimonidine either for congenital glaucoma or by accidental ingestion. See also Contraindications. COMBIGAN® brimonidine tartrate/timolol Datasheet Version 6.0-CCDS v3.1 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and other adult patients. In a brimonidine only study evaluating the accumulation of brimonidine tartrate in plasma following dosing of brimonidine tartrate alone, the Cmax and apparent half-life of brimonidine were similar in elderly subjects (65 years or older) and younger adults, indicating that its systemic absorption and elimination were not significantly affected by age. 4.3 Contraindications COMBIGAN® eye drops are contraindicated in patients with hypersensitivity to brimonidine tartrate, timolol maleate or any of the excipients listed in section 6.1. In patients receiving monoamine oxidase (MAO) inhibitor therapy, in patients with bronchospasm, bronchial asthma or patients with a history of bronchial asthma, or severe chronic obstructive pulmonary disease, in patients with sinus bradycardia, sick sinus syndrome, sinoatrial nodal block, second or third degree atrioventricular block not controlled with a pacemaker, overt cardiac failure or cardiogenic shock. Patients who have been receiving MAO inhibitor therapy should wait 14 days after discontinuation before commencing therapy. COMBIGAN® eye drops are also contraindicated in neonates and infants, ie children under the age of 2 years. 4.4 Special warnings and precautions for use General Like other topically applied ophthalmic agents, COMBIGAN® may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur. Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease (e.g. coronary heart disease, Prinzmetal’s angina and cardiac failure) and hypotension. Cardiac failure should be adequately controlled before beginning therapy. Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can in some cases lead to cardiac failure. At first sign or symptom of cardiac failure, COMBIGAN® should be discontinued. Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure have been reported following administration of timolol maleate. Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block. COMBIGAN® brimonidine tartrate/timolol Datasheet Version 6.0-CCDS v3.1 Children 2 years of age and above, especially those weighing ≤ 20 kg, should be treated with caution and closely monitored due to the high incidence and severity of somnolence. COMBIGAN® eye drops have not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients. In patients with severe renal impairment on dialysis, treatment with timolol has been associated with pronounced hypotension. COMBIGAN® eye drops should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans. Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection) or any ocular reactions, particularly conjunctivitis and lid reactions, they should immediately seek their doctor’s advice concerning the continued use of the product. Beta-blockers may also mask the clinical signs of hyperthyroidism (e.g. tachycardia) and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm. Patients who are already receiving a beta-adrenergic blocking agent orally and who are given timolol should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade. The use of two topical beta-adrenergic blocking agents is not recommended. COMBIGAN® should not be used alone in the treatment of acute angle-closure glaucoma. Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution. Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedure. While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated accidental, diagnostic or therapeutic challenge with such allergens and may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions. Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents as beta-blockers may mask the signs and symptoms (e.g. tachycardia) of acute hypoglycaemia. COMBIGAN® brimonidine tartrate/timolol Datasheet Version 6.0-CCDS v3.1 Beta-adrenergic receptor blockade impairs the ability of the heart to respond to betaadrenergically mediated reflex stimuli. This may augment the risk of general anaesthesia in surgical procedures. In patients undergoing elective surgery, it may be necessary to gradually withdraw the beta-adrenergic receptor blocking agents. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists. Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalised weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with COMBIGAN®, alternate therapy should be considered. Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which timolol is contraindicated [see Contraindications]) should, in general, not receive products containing beta-blockers, including COMBIGAN® however, if COMBIGAN® is deemed necessary in such patients, it should be administered with caution Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solution 0.2%, with some reported to be associated with an increase in IOP. Preclinical Findings Carcinogenicity, Mutagenicity and Impairment of Fertility No study has been conducted to investigate the carcinogenicity, mutagenicity or effects on fertility of COMBIGAN®. The following information is based on studies with